Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems. Muscarinic receptors comprise five distinct subtypes, denoted as muscarinic M1, M2, M3, M4 and M5 receptors. Each subtype has a unique distribution in the central and peripheral nervous systems. The M1 receptor is predominantly expressed in the cerebral cortex and is believed to be involved in the control of higher cognitive functions; the M2 receptor is the predominant subtype found in heart and is involved in the control of heart rate; the M3 receptor is widely expressed in many peripheral tissues and is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; the M4 receptor is present in the brain and may be involved in locomotion and antipsychotic effects; the M5 receptor is located in the brain and may be involved in compound addition and in psychotic conditions such as schizophrenia. In view of the key physiological roles attributed to each of the muscarinic receptor subtypes, extensive efforts have been made to generate new compounds showing selective agonistic or antagonistic properties (see for example EP 0296721; EP 0316718; Sauerberg, P. et al., J. Med. Chem., 1992, Vol. 35, No. 22, 2274-2283; Ward, J. S. et al., 1992, J. Med. Chem., Vol. 35, No. 22, 4011-4019; U.S. Pat. No. 5,527,813; Zlotos, D. P. et al., Exp. Opin. Ther. Patents, Vol. 9, No. 8, 1999, 1029-1053; Plate, R., et al., Bioorg. Med. Chem. 4 (1996), 227-237; Plate, R. et al., Bioorg. Med. Chem. 8 (2000), 449-454; Del Guidice, M. R. et al., Arch. Pharm. Med. Chem. 2003, 336, 143-154).
A well known example of a M1/M4 preferring muscarinic receptor agonist is the thiadiazole compound xanomeline which in preclinical studies has a desirable profile, however, in clinical studies displays a unfavourable side effects (see for example the review by Eglen, R. M., Progress in Medicinal Chemistry, 2005, 43, p. 105-136 and U.S. Pat. No. 5,376,668), which seem to be related to M2 receptor mediated activity (e.g. heart rate effects). In addition, xanomeline has a relatively low (in vitro) metabolic stability. Xanomeline related compounds are further disclosed in U.S. Pat. No. 5,527,813. However, representative compounds display unfavourable side effects which seem to be related to M2 and M3 receptor mediated activity (e.g. heart rate effects and salivation, respectively).
Although further research is ongoing to develop therapeutics that have the selective M1/M4 profile, this has not yet resulted in successful candidates. Therefore, there is a need for new selective compounds with the desired properties.